Nasal NK/T-cell lymphoma: epidemiology and pathogenesis
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- Aozasa, K., Takakuwa, T., Hongyo, T. et al. Int J Hematol (2008) 87: 110. doi:10.1007/s12185-008-0021-7
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Nasal NK/T-cell lymphoma (NKTCL) is an uncommon disease, but usually shows a highly aggressive clinical course. The disease is much more frequent in Asian and Latin American countries than in Western countries, and is universally associated with Epstein–Barr virus (EBV) infection. Analyses of gene mutations, especially p53 and c-KIT, revealed the different frequencies by district. Epidemiological studies revealed the changes of the disease frequency in Korea during the period from 1977–1989 to 1990–1996. Case-control study showed that the exposure to pesticides and chemical solvents could be causative of NKTCL. Further studies including HLA antigen typing of patients is necessary to further clarify the disease mechanism.
KeywordsNasal lymphomaNK/T-cell typeEpstein–Barr virusp53 genec-KIT genePesticideEpidemiology
Rapid destruction of the nose and face (midline) was firstly described by McBride in 1897 . Macroscopically the lesions usually looked like necrotic granuloma and the patients showed aggressive and lethal course, therefore the term “lethal midline granuloma (LMG)” or “granuloma gangrenescens” were used for this condition. Later the term LMG is popularly used. It had became evident that the LMG is composed of three different types of histology, i.e. Wegener’s granulomatosis (WG), polymorphic reticulosis (PR) or midline malignant reticulosis (MMR), and malignant lymphoma [2, 3]. These diseases could be histologically differentiated from each other by taking clinical findings into account. WG is usually characterized by generalized necrotizing vasculitis involving both arteries and veins and the presence of glomerulitis . Cancer and specific inflammation such as tuberculosis also cause a condition indistinguishable from LMG.
1 Association with Epstein–Barr virus (EBV)
As shown in Table 1, the proliferating cells in NKTCL frequently express latent membrane protein (LMP) as revealed by immunohistochemistry. Latent infection gene products of EBV, EBNA-2 and LMP-1, serve as target antigens for the elimination of EBV infected cells by host cytotoxic T-lymphocytes (CTL) . Shen et al.  showed that NKTCL cells are able to provide target epitopes of EBV for CTL. In immunocompromised hosts, proliferating cells expressing EBNA-2 and LMP-1 can escape from immune surveillance by the host CTL, which might result in the development of malignant lymphomas . However, systemic immunosuppression is not noted in patients with NKTCL, thus suggesting an unknown underlying mechanism for escape of LMP-1-expressing tumor cells from the CTL. Several mechanisms such as downregulation of the immunogenic EBV nuclear antigens and preferential selection of the deletion genotype of LMP-1 was reported by Chiang et al. [33, 34] and expression of IL-10, an immunosuppressive cytokine, was reported by Shen et al. . The cells expressing viral antigens are eliminated primarily by CTL in a MHC-class-I-restricted manner . Two CTL-epitopes were identified in LMP-1 that are possibly pan A*02-restricted . It is possible that NKTCL patients show lower frequencies of A*02 allele compared with those in the normal population. Indeed high-resolution genetic typing revealed significantly lower frequency of HLA-A*0201 in NKTCL than in normal population . These findings suggest that HLA-A*0201-restricted CTL responses may function in vivo to suppress the development of NKTCL, or in other words, role of EBV for NKTCL development.
2 Genetical changes
Lymphoma arises from clonal expansion of lymphoid cells that are transformed by the accumulation of genetic lesions affecting oncogenes and tumor suppressor genes. In general, amount of samples from NKTCL lesions available for genetical analyses is small, and samples usually contain massive necrotic areas. Therefore information for genetical changes in NKTCL has been relatively limited until present.
2.1 Alterations of tumor suppressor genes and oncogenes
Quintanilla-Martinez et al. reported the association of p53 overexpression with poor prognosis, and p53 mutations with large cell morphology and advanced stage [43, 48]. However these findings were not confirmed by other studies. [15, 38]
The c-KIT proto-oncogene encodes a receptor tyrosine kinase, which is involved in normal hematopoiesis, gametogenesis, and melanogenesis via the c-kit receptor-ligand system. . Because the development of acute leukemia or malignant lymphoma was reported in transgenic mice expressing KIT [8, 14, 50], NKTCL in Asian countries was examined for the c-kit gene mutations . Frequency of c-kit mutations was significantly higher in China (Beijing, Chengdu) (10 of 14 cases: 71.4%)  than in Japan (9 of 58 cases: 15.5%) , Korea (5 of 42 cases:11.9%) , northeast China (Shenyang) (2 of 20 cases:10%) , and Indonesia (3 of 27 cases :11.1%) . These findings suggest that location-specific differences in etiological factors cause specific mutations in c-kit gene.
2.2 FAS Gene Mutations
Various cytogenetic alterations have been reported, of which deletions of 6q are the common .
3 Epidemiological features
Frequency of lethal midline granuloma in Japan, Korea (Seoul), and China (Shanghai)
Number of patients (frequency per 100,000 ENT patients)
Japan other than Okinawa (1965–1986)
At the late 1990s, otorhinolaryngologists in both Korea and Japan had the impression that the frequency of PR appeared to be decreasing. Then the changes in frequency of PR with time among cases from Seoul and 59 university hospitals in Japan were examined : the frequency rate of PR per 100,000 outpatients of ENT clinics in Seoul decreased from 40 to 20 between the periods of 1977–1989 and 1990–1996. However, there were no significant changes in Japan during the period studies.
3.1 Life-style and environmental factors
Risk of nasal NK/T-cell lymphoma in relation to cultivation of crops and pesticide use
Odds ration (OR)a
Number of cases N = 88
Number of controls N = 305
Cultivation of crops
More than 5 years
Type of pesticide
Gloves not used
Mask not used
Glasses not used
Sprinkling downward attended
Sprinkling downward not attended
Clinical course of patients with NKTCL is usually highly aggressive. Therefore clarification of risk factors for disease development is especially important to establish a strategy for disease prevention. Because EBV infection and pesticides could be risk factors for NKTCL, investigation on effects of pesticides for EBV activation is needed. Employment of the similar kind of the epidemiological study is desirable in other areas than East Asia. Patients with NKTCL cluster in Asia and Latin American countries, therefore some genetical factors might be involved in the disease development. Further studies including HLA antigen typing of patients is important to further clarify the mechanism for disease development.